Invertebrate models of spinal muscular atrophy: Insights into mechanisms and potential therapeutics

Grice, Stuart J.; Sleigh, James N.; Liu, Ji‐Long; Sattelle, David B.

doi:10.1002/bies.201100082

Cited by 24 publications

(25 citation statements)

References 88 publications

(131 reference statements)

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“…We show a similar interaction profile in Drosophila . Notably, we reveal that Gaulos/Gemin4 and Valette/Gemin8 are essential for neuromuscular survival and function in line with reports describing a similar requirement for SMN and Gemin2/3/5 . Besides constituting evidence favouring these two proteins as the bona fide Drosophila orthologues of the respective Gemin counterparts in vertebrates, these findings also expose a novel in vivo function in the motor system for Gemin4 and Gemin8.…”

Section: Discussionsupporting

confidence: 90%

Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

et al. 2017

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The Spinal Muscular Atrophy disease protein Survival Motor Neuron (SMN) operates as part of a multiprotein complex whose components also include Gemins 2-8 and Unrip. The fruit fly Drosophila melanogaster is thought to have a slightly smaller SMN complex comprised of SMN, Gemin2/3/5 and, possibly, Unrip. Based upon in vivo interaction methods, we have identified novel interacting partners of the Drosophila SMN complex with homologies to Gemin4/6/7/8. The Gemin4 and Gemin8 orthologues are required for neuromuscular function and survival. The Gemin6/7/Unrip module can be recruited via the SMN-associated Gemin8, hence mirroring the human SMN complex architecture. Our findings lead us to propose that an elaborate SMN complex that is typical in metazoans is also present in Drosophila.

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Section: Discussionsupporting

confidence: 90%

Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

et al. 2017

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“…In the cytoplasm, SMN complexes and uridine-rich snRNPs often aggregate in U bodies, which are thought to play a role in snRNP assembly and/or storage [1,26,38-40]. On staining for their TMG cap, snRNPs are concentrated in discrete spherical structures dotting the wild type nurse cell cytoplasm (Figure 4E).…”

Section: Methodsmentioning

confidence: 99%

Conserved requirement for DEAD-box RNA helicase Gemin3 in Drosophila oogenesis

Cauchi

2012

BMC Res Notes

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BackgroundDEAD-box RNA helicase Gemin3 is an essential protein since its deficiency is lethal in both vertebrates and invertebrates. In addition to playing a role in transcriptional regulation and RNA silencing, as a core member of the SMN (survival of motor neurons) complex, Gemin3 is required for the biogenesis of spliceosomal snRNPs (small nuclear ribonucleoproteins), and axonal mRNA metabolism. Studies in the mouse and C. elegans revealed that loss of Gemin3 function has a negative impact on ovarian physiology and development.FindingsThis work reports on the generation and characterisation of gemin3 mutant germline clones in Drosophila adult females. Gemin3 was found to be required for the completion of oogenesis and its loss led to egg polarity defects, oocyte mislocalisation, and abnormal chromosome morphology. Canonical Cajal bodies were absent in the majority of gemin3 mutant egg chambers and histone locus bodies displayed an atypical morphology. snRNP distribution was perturbed so that on gemin3 loss, snRNP cytoplasmic aggregates (U bodies) were only visible in wild type.ConclusionsThese findings establish a conserved requirement for Gemin3 in Drosophila oogenesis. Furthermore, in view of the similarity to the phenotypes described previously in smn mutant germ cells, the present results confirm the close functional relationship between SMN and Gemin3 on a cellular level.

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“…To study the pathomechanisms of this devastating disease, a large number of invertebrate animal and mouse models have been generated (for detailed reviews, see Grice et al, 2011; Park et al, 2010; Sleigh et al, 2011). By investigating the morphological and cellular defects characterizing these models, several laboratories have gained valuable insight into the unique role of SMN in motor neuron development and survival.…”

Section: Sma As An Axonopathymentioning

confidence: 99%

Spinal muscular atrophy: The role of SMN in axonal mRNA regulation

2012

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Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous mutations or deletions in the survival of motor neuron (SMN1) gene, encoding the ubiquitously expressed SMN protein. SMN associates with different proteins (Gemins 2-8, Unrip) to form a multimeric complex involved in the assembly of small nuclear ribonucleoprotein complexes (snRNPs). Since this activity in essential for the survival of all cell types, it still remains unclear why motor neurons are selectively vulnerable to low levels of SMN protein. Aside from its housekeeping role in the assembly of snRNPs, additional functions of SMN have been proposed. The well-documented localization of SMN in axonal transport granules and its interaction with numerous mRNA-binding proteins not involved in splicing regulation suggest a role in axonal RNA metabolism. This review will focus on the neuropathological and experimental evidence supporting a role for SMN in regulating the assembly, localization, or stability of axonal messenger ribonucleoprotein complexes (mRNPs). Furthermore, how defects in this non-canonical SMN function may contribute to the motor neuron pathology observed in SMA will be discussed.

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Invertebrate models of spinal muscular atrophy: Insights into mechanisms and potential therapeutics

Cited by 24 publications

References 88 publications

Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

Conserved requirement for DEAD-box RNA helicase Gemin3 in Drosophila oogenesis

Spinal muscular atrophy: The role of SMN in axonal mRNA regulation

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